The present invention relates to the use of a microutrophin coding sequence in the treatment of muscular dystrophy.
Duchenne Muscular Dystrophy (DMD) is caused by a deficiency of the muscle cytoskeletal protein known as dystrophin. Dystrophin is a member of the spectrin superfamily of proteins and as such is distantly related to spectrin and alpha-actinin. Dystrophin is most closely related to the protein utrophin. The genes for these two proteins have nearly identical intron/exon structures, and the proteins are 50+% homologous at the amino acid level. Dystrophin is expressed throughout the entire length of the skeletal muscle fiber while utrophin is normally expressed only at the neuromuscular junction. Most cases of DMD result from sporadic deletions of the X chromosomal dystrophin gene. The destruction of the dystrophin open reading frame by these mutations suggests that therapies that genetically reconstitute dystrophin expression will elicit a cellular immune response against the fibers in which the protein is synthesized.
In the years following the initial discovery of utrophin, the technologies for targeted gene ablation in mice facilitated a formal genetic analysis of gene complementation. In the transgenic mouse in which the expression of utrophin is dictated by a muscle-specific promoter, utrophin can complement the physiological role of dystrophin.
Tinsley and Davies, U.S. Pat. No. 6,518,413, describe the expression of a polypeptide with utrophin function from a nucleic acid sequence for use in treatment of muscular dystrophy. This group designed a truncated protein modeled on a natural mutation identified in a mild Becker muscular dystrophy patient. However, while the constructs provide some amelioration of symptoms, they are not optimal in terms of size, permissible delivery routes, or therapeutic outcome.
More recently, X. Xiao, US Patent Application Publn No. US 2003/0171312 A1 and J. Chamberlain, et al, US Patent Application Publn No. US 2003/0216332 A1, have described mini-dystrophin genes for use in treating muscular dystrophies. In the case of US 2003/0171312 A1, the dystrophin mini-gene may contain regions of the utrophin gene.
What is needed is an improved method of treating muscular dystrophies.